Squamous cell cancer of the oral cavity is a devastating disease in which the present therapies result in severe functional and cosmetic deformities. The primary objective of this project is to develop a new treatment modality for oral cancer which results in improved survival and less morbidity than standard surgery, radiation, or chemotherapy. The new treatment is based on a replication defective adenoviral vector that will transfer select therapeutic genes into established oral tumors. Adenoviral-mediated transfer of the "suicide gene", herpes thymidine kinase (tk), will result in direct cancer cell death, but in previous studies, has not resulted in long-term tumor eradication in more than 50% of experimental animals. Two cytokine genes which stimulate anti-tumor immune responses have therefore been chosen to investigate the synergistic effects of their actions in combination with the tk gene transfer. Local secretion of interleukin-2 (IL-2) has been effective in stimulating cytotoxic T-cell responses and causing tumor regression . Local secretion of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) results in helper T-cell stimulation and induces systemic anti-tumor immunity. A synergistic effect between the direct cancer cell killing of tk and the anti-tumor immune responses of IL-2 and GM-CSF should provide a powerful new treatment regimen for oral cancer. We will test our hypothesis that gene transfer can be effectively used to treat oral squamous cell carcinoma by addressing the following specific aims: 1) Maximize the efficacy of adenoviral-mediated delivery of the herpes thymidine kinase gene; 2) Determine the effects of cytokine gene transfer alone and in combination with tk therapy; and 3) Define the mechanism of active immunization against oral cavity carcinoma after adenoviral-mediated gene transfer. We anticipate that our investigations in this novel therapy will provide the foundation for innovative clinical trials in our oral cancer patient population.